Creatine (Cr), or 2-(carbamimidoyl-methyl-amino) acetic acid, is a naturally occurring nitrogenous organic acid that is synthesized in the liver of vertebrates and helps to supply energy to muscle and nerve cells. Creatine is synthesized from the amino acids arginine, methionine, and glycine through a two-step enzymatic process involving GAMT (guanidinoacetate N-methyltransferase, also known as glycine amidinotransferase) by methylation of guanidoacetate using S-adenosyl-L-methionine (SAM) as the methyl donor. Guanidoacetate itself is formed in the kidneys from the amino acids arginine and glycine. Once made in the liver or acquired through digestion, creatine is stored in cells including muscle and brain cells.
The enzyme creatine (phospho)kinase (CPK or CK), catalyzes the transfer of the phosphate from ATP to the guanidinium of creatine, forming creatine phosphate (PCr). The reaction is reversible, such that when energy demand is high (e.g., during muscle exertion or brain activity), CPK can dephosphorylate creatine phosphate and transfer the phosphate back to ADP forming ATP. This enables creatine to act as an energy storage molecule where phosphate can be stored independently of ATP.
Perturbed mitochondrial function can lead to ATP depletion, resulting in significant physiological problems. One potential method of addressing ATP depletion is to increase phosphocreatine (PCr) stores, for example by administering creatine which can be phosphorylated by CPK. Several forms of CPK exist but the most ubiquitous form of the enzyme resides in the mitochondrion, where it produces phosphocreatine from mitochondrially-generated ATP and creatine from the cytosol. However, creatine transport to the mitochondrion is an energy requiring process. Accordingly, a need remains for creatine analogs targeted to the mitochondrion to circumvent the energy loss associated with endogenous creatine transport and to provide creatine at the subcellular location of creatine action.